This invention pertains to modification of T lymphocytes for therapy, research, and other uses. The T cell modifications enhance T lymphocyte survival.
Adoptive T lymphocyte transfer (adoptive immunotherapy) is the transfer of T lymphocytes to a subject for the therapy of disease. It has great potential for the therapy of a wide variety of diseases including cancer and infectious diseases. Adoptive immunotherapy takes advantage of the immune response, in which the T lymphocyte plays a central role.
The immune response is often thought of as having distinct phases. These phases have been referred to as the initiation, expansion, contraction, and maintenance or memory phases (Schuluns & Lefrancois, Nature Rev. 3:269-79 (2003)). After an antigen is recognized, the immune response is “initiated.” This is followed by a rapid increase in the number of cells participating in the immune response during the “expansion phase.” Without expansion the immune response tends to be ineffective. The next phase, the “contraction phase,” controls the size of the immune response to prevent an excessive response that might damage the host. Apoptosis, a specific type of programmed cell death, is an important cellular process during the contraction phase of the immune response. If contraction is excessive, a short-lived and/or weak immune response can result. Finally, for sustained immunity, the immune response must enter the “maintenance phase” and generate “memory T lymphocytes.”
An obstacle limiting the efficacy of adoptive immunotherapy is the short-lived survival of the transferred cells. For example, in vitro activation is a step frequently employed in adoptive immunotherapy, but in vitro activated T lymphocytes tend to undergo apoptosis upon in vivo transfer. IL-2 has been given to patients to stimulate their immune response in general, and to augment adoptive immunotherapy. IL-2 does not enhance the survival of T lymphocytes during the contraction stage of the immune response or favor the formation of T lymphocytes, but may be used to prolong or continue the expansion phase. IL-2, however, has significant toxicities when administered to patients and patients cannot always tolerate sufficient amounts of IL-2 required for optimum adoptive immunotherapy. Toxicities associated with high-dose IL-2 include chills, nausea, vomiting, diarrhea, and “capillary-leak syndrome” (which can require intensive care). In addition, patients undergoing high-dose IL-2 therapy frequently also receive prophylactic antibiotic therapy.
The foregoing shows that there is a need to improve adoptive immunotherapy.
The present invention attenuates this need by providing T lymphocytes with enhanced survival during the contraction phase of the immune response, and compositions comprising the same. Advantageously, the invention attenuates the needs in the art by a method that can avoid the toxicity associated with conventional high-dose IL-2 therapy. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.